Effects of Low-intensity Exercise on Pulmonary Arterial Hypertension: A Comprehensive Transcriptomic Analysis of Lung, Heart and Muscle

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Abstract Low-intensity training in patients with pulmonary arterial hypertension (PAH) has been shown to improve quality of life, exercise capacity, and hemodynamics. However, the effects vary between individuals by mechanisms that remain poorly understood. In this study, a murine model of PAH, induced by SU5416 and hypoxia, was used to explore gene expression changes in the lungs, heart, and gastrocnemius muscle following a daily 45-minute exercise regimen. The goal is to identify novel biomarkers that could help assess functional status. Four groups were included: Exercise-Non PAH (E-NoPAH, n=6) and Exercise-PAH (E-PAH, n=6), alongside Sedentary-PAH (S-PAH, n=6) and Sedentary-Non PAH (S-NoPAH, n=6) counterparts. Systolic pulmonary arterial pressure (sPAP) was measured via right heart catheterization. Gene expression analysis was conducted using the Affymetrix GeneChip™ Mouse Gene 2.0 ST Array platform. Genes were considered differentially expressed (DEGs) if |FC| ≥ 1.5 with a P<0.05 and FDR<0.2. For each organ, three comparisons were made: E-NoPAH vs. S-NoPAH, S-PAH vs. S-NoPAH, and E-PAH vs. S-PAH, with functional annotations based on REACTOME data for DEGs. S-PAH group showed increased levels of sPAP and significant changes in a large number of genes (UP- and DW-regulated) compared to S-NoPAH, most notably in the lung (497 total DEGs) compared with the heart (156) and muscle (175), and with more upregulated than downregulated genes in all tissues. Low-intensity exercise in non-PAH animals also induced significant changes in a number of genes in all tissues, with a greater number in gastrocnemius (80) than in the heart (5) and lung (21) without changes in sPAP. In contrast, low-intensity exercise in PAH animals induced a significant reduction in sPAP. In particular, animals from this group had a lower number of DEGs in the lung (448 vs 497) and gastrocnemius (121 vs 175) but not in the heart (164 vs 156) compared with sedentary PAH animals. E-PAH group showed a downregulation of DEGs in the lung associated with key functional annotations such as cell proliferation, cell adhesion and angiogenesis (p<0.05). In conclusion, in a murine model of PAH, exercise did not exert a synergistic effect on the molecular pathways activated by pulmonary hypertension. On the contrary, we observed a downregulation of genes previously activated by the hypertensive stimulus particularly in the lung. The greater downregulation of exercise-induced genes in the lung, but not in the heart, suggests greater pulmonary benefit of low-intensity exercise in the context of PAH.

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